1 NAC Proposed 1: June 2009 2 3 4 5 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)

6 FOR

7 ALDICARB

8 (CAS Reg. No. 116-06-3) 9

10 11 12 13 14 PROPOSED 15 16 17 ALDICARB NAC Proposed 1: June 2009/ Page 2 of 33

1 2 PREFACE 3 4 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 5 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 6 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 7 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 8 chemicals. 9 10 AEGLs represent threshold exposure limits for the general public and are applicable to 11 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels – AEGL-1, 12 AEGL-2 and AEGL-3 – are developed for each of five exposure periods (10 and 30 minutes, 1 13 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 14 The three AEGLs are defined as follows: 15 16 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 17 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 18 population, including susceptible individuals, could experience notable discomfort, irritation, or 19 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 20 transient and reversible upon cessation of exposure. 21 22 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 23 which it is predicted that the general population, including susceptible individuals, could 24 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 25 to escape. 26 27 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 28 which it is predicted that the general population, including susceptible individuals, could 29 experience life-threatening health effects or death. 30 31 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 32 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 33 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 34 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 35 severity of effects described for each corresponding AEGL. Although the AEGL values 36 represent threshold levels for the general public, including susceptible subpopulations, such as 37 infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized 38 that individuals, subject to unique or idiosyncratic responses, could experience the effects 39 described at concentrations below the corresponding AEGL. 40

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1 TABLE OF CONTENTS

2 PREFACE...... 2

3 LIST OF TABLES...... 5

4 SUMMARY...... 6

5 1. INTRODUCTION...... 7

6 2. HUMAN TOXICITY DATA...... 8

7 3. ANIMAL TOXICITY DATA...... 9

8 3.1. Acute Toxicity...... 9 9 3.2. Repeat-Exposure Studies...... 10 10 3.3. Neurotoxicity...... 10 11 3.4. Developmental/Reproductive Toxicity...... 11 12 3.5. Genotoxicity ...... 11 13 3.6. Chronic Toxicity/Carcinogenicity ...... 11 14 3.7. Summary...... 11

15 4. SPECIAL CONSIDERATIONS ...... 12

16 4.1. Metabolism and Disposition...... 12 17 4.2. Mechanism of Toxicity...... 12 18 4.3. Structure-Activity Relationships...... 13 19 4.4. Other Relevant Information...... 14 20 4.4.1. Species Variability...... 14 21 4.4.2. Susceptible Populations...... 15 22 4.4.3. Concentration-Exposure Duration Relationship ...... 15 23 4.4.4. Concurrent Exposure Issues...... 16

24 5. DATA ANALYSIS FOR AEGL-1 ...... 16

25 5.1. Summary of Human Data Relevant to AEGL-1...... 16 26 5.2. Summary of Animal Data Relevant to AEGL-1...... 16 27 5.3. Derivation of AEGL-1...... 16

28 6. DATA ANALYSIS FOR AEGL-2 ...... 16

29 6.1. Summary of Human Data Relevant to AEGL-2...... 16 30 6.2. Summary of Animal Data Relevant to AEGL-2...... 16 31 6.3. Derivation of AEGL-2...... 16

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1 7. DATA ANALYSIS FOR AEGL-3 ...... 17

2 7.1. Summary of Human Data Relevant to AEGL-3...... 17 3 7.2. Summary of Animal Data Relevant to AEGL-3...... 17 4 7.3. Derivation of AEGL-3...... 17

5 8. SUMMARY OF AEGLs...... 18

6 8.1. AEGL Values and Toxicity Endpoints...... 18 7 8.2. Comparison with Other Standards and Guidelines...... 18 8 8.3. Data Adequacy and Research Needs ...... 20

9 9. REFERENCES...... 20

10 APPENDIX A: Derivation of Aldicarb AEGLs ...... 23

11 APPENDIX B: Category Graph of AEGL Values and Toxicity Data...... 25

12 APPENDIX C: Benchmark Concentration Calculations for Aldicarb...... 27

13 APPENDIX D: Derivation Summary for Aldicarb AEGLs...... 31

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1 LIST OF TABLES 2 TABLE ES 1. Summary of AEGL Values for Aldicarb ...... 7 3 TABLE 1. Chemical and Physical Properties...... 8 4 TABLE 2. Acute Toxicity of Aldicarb to Rats...... 10 5 TABLE 3. Adult Rat and Human BMD10 and BMDL10 Values for Cholinesterase Activity Inhibition for N- 6 Methyl Carbamate Pesticides (Oral Dosing)...... 13 7 TABLE 4. Comparison of Erythrocyte Acetylcholinesterase Activity Inhibition in Rats and Humans...... 14 8 TABLE 5. AEGL-1 Values for Aldicarb...... 16 9 TABLE 6. AEGL-2 Values for Aldicarb...... 17 10 TABLE 7. AEGL-3 Values for Aldicarb...... 18 11 TABLE 8. Summary of AEGL Values for Aldicarb...... 18 12 TABLE 9. Standards and Guidelines for Aldicarb...... 19 13

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1 SUMMARY 2 3 Technical aldicarb (CAS No. 116-06-3) is a crystalline solid N-methyl carbamate 4 pesticide with a slight sulfur smell. Aldicarb is registered as a systemic insecticide, acaricide, 5 and nematocide for use on a wide range of crops. Aldicarb, sold under the trade name Temik™, 6 is a granular formulation containing 5, 10, or 15% active ingredient. Temik™ is usually applied 7 below the soil surface for absorption by plant root systems. Moisture is required to release the 8 active ingredient from the granules. Two soil degradates, aldicarb sulfoxide and aldicarb 9 sulfone, retain some of the toxic property of the parent compound. Approximately 4.5 million 10 pounds of aldicarb are used annually in the United States. 11 12 Aldicarb and other carbamate pesticides are neurotoxic in that they are inhibitors of 13 cholinesterase enzymes. Inhibition of acetylcholinesterase, responsible for termination of the 14 biological activity of the neurotransmitter acetylcholine at various nerve endings, results in 15 sustained stimulation of electrical activity. Depending on concentration administered, signs 16 following acute exposure of rats to aldicarb may include facial fasciculations, tremors, 17 salivation, lacrimation, gasping and convulsions. In humans, inhibition of erythrocyte 18 acetylcholinesterase activity, the form found in human erythrocytes, is used as a biomarker of 19 exposure to methyl carbamates. No inhalation studies involving human subjects were located. 20 Given that methyl carbamate pesticides do not have a port of entry effect, are expected to be 21 rapidly absorbed, and do not require activation, relative acetylcholinesterase activity inhibition 22 levels measured from oral studies with humans and adult and juvenile rodents are applicable for 23 determination of interspecies and intraspecies uncertainty factors. 24 25 No human data relevant to derivation of AEGL values were found. No animal studies 26 were located that addressed effects of aldicarb consistent with the definition of the AEGL-1. 27 Therefore, AEGL-1 values are not recommended. 28 29 No studies that addressed effects consistent with the definition of the AEGL-2 were 30 found. The concentration-response curve for lethality in rats is steep as shown by the studies of 31 Risher et al. (1987) and UCC (1985). Mortality went from 0 to 83% with the doubling of 32 exposure duration (Risher et al. 1987). Therefore, according to Standard Operating Procedures 33 (NRC 2001), the AEGL-2 values were derived by dividing the AEGL-3 values by 3. 34 35 The study with aldicarb aerosol (UCC 1985) was chosen as the key study for AEGL-3 36 development. The 4-hour study used a sufficient number of rats and five concentrations. The 3 3 37 calculated 4-hour BMCL05 is 0.97 mg/m and the BMC01 is 1.9 mg/m . The 4-hour BMCL05 was 38 chosen as the threshold for lethality. The 4-hour 0.97 mg/m3 value was divided by inter- and 39 intraspecies uncertainty factors of 2 and 3, respectively, for a total of 6. The aldicarb-specific 40 interspecies inhalation uncertainty factor of 2 was based on differences in modeled values for red 41 blood cell acetylcholinesterase activity inhibition between rats and humans (U.S. EPA 2007b). 42 The intraspecies uncertainty factor of 3, derived by U.S. EPA (2007b) for the related methyl 43 carbamates, oxamyl and methomyl, was applied. The intraspecies uncertainty factor was based 44 on comparative brain acetylcholinesterase activity inhibition in juvenile and adult rats 45 administered the pesticides by the oral route. The combined uncertainty factor is 6. No 46 information was available for time-scaling. Values were time-scaled (Cn x t = k) from the 4-hour

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1 data point using n values of 3 and 1 for extrapolation to shorter and longer exposure durations, 2 respectively (NRC 2001). 3 4 The calculated values are listed in the table below. 5 TABLE ES 1. Summary of AEGL Values for Aldicarb

Classification 10-min 30-min 1-h 4-h 8-h Endpoint (Reference) AEGLB1 Not Not Not Not Not Insufficient data (Nondisabling) recommended recommended recommended recommended recommended AEGLB2 0.16 mg/m3 0.11 mg/m3 0.087 mg/m3 0.053 mg/m3 0.027 mg/m3 AEGL-3 values (Disabling) divided by 3 3 3 3 3 3 AEGLB3 0.47 mg/m 0.32 mg/m 0.26 mg/m 0.16 mg/m 0.081 mg/m BMCL05 for lethality – (Lethal) rat - calculated from UCC (1985) data Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 6 7 1. INTRODUCTION 8 9 Technical aldicarb (CAS No. 116-06-3) is a white crystalline solid with a slight sulfur 10 smell (AIHA 1993). Aldicarb is registered for use as a systemic insecticide, acaricide, and 11 nematocide on a wide range of crops (O’Neil et al. 2001; U.S. EPA 2007a). Aldicarb is sold in 12 the United States under the trade name Temik™, a granular formulation of aldicarb containing 5, 13 10, or 15% a.i. (active ingredient by weight) aldicarb in corn cob grit or gypsum; 14 dichloromethane may be present up to 0.2% (UCC 1986). Temik™ is usually applied below the 15 soil surface for absorption by plant root systems. Moisture is required to release the active 16 ingredient from the granules. Two soil degradates, aldicarb sulfoxide and aldicarb sulfone retain 17 anti-cholinesterase activity. Chemical and physical properties are listed in Table 1. 18 19 Aldicarb is manufactured commercially by the reaction of methyl isocyanate with 2- 20 methyl-2-(methylthio) propionaldehyde (HSDB 2005). According to U.S. EPA (2007a), 21 approximately 4.5 million pounds of aldicarb are used annually in the United States, primarily on 22 cotton (64%). Other high use crops include peanuts, potatoes, sugar, beets, and citrus. World 23 production figures are not available (IPCS 1991). Aldicarb is a restricted use pesticide and can 24 be applied only by certified applicators. 25

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TABLE 1. Chemical and Physical Properties Parameter Value Reference Synonyms 2-Methyl-2-(methylthio)-propanal O- O’Neil et al. 2001 [(methylamino)carbonyl]oxime; 2- methyl-2-(methylthio)- propionaldehyde O- (methylcarbamoyl)oxime; Temik™

Chemical formula C7H14N2O2S O’Neil et al. 2001 Molecular weight 190.27 O’Neil et al. 2001 CAS Reg. No. 116-06-3 O’Neil et al. 2001 Physical state Aldicarb: white crystalline solid AIHA 1993 Temik 15G pesticide: UCC 1986 brown to black crystals Solubility in water Soluble, 6 g/L at 25ºC O’Neil et al. 2001; AIHA 1993 Vapor pressure, saturated 0.0001 mm Hg at 25ºC AIHA 1993 Vapor density, saturated (air =1) 0.1 ppm at 25ºC AIHA 1993 Liquid density (water =1) 1.195 at 25ºC AIHA 1993 Melting point 99-100 ºC O’Neil 2001 Boiling point Decomposes AIHA 1993 Flammability limits in air No data Conversion factors 1 ppm = 7.78 mg/m3 Calculated 1 mg/m3 = 0.13 ppm 1 2 3 2. HUMAN TOXICITY DATA 4 5 No inhalation studies other than descriptions of accidental exposures were located. 6 These reports lacked information on concentrations and exposure durations. Symptoms of 7 cholinesterase activity inhibition have been observed following ingestion of food containing 8 aldicarb or aldicarb degradates (HSDB 2005). 9 10 A double-blind human oral dosing study included 47 volunteers (38 men and 9 women) 11 (Wyld et al. 1991, reviewed in U.S. EPA 1992). Groups of 4-8 males were administered doses 12 of 0, 0.01, 0.025, 0.05, 0.06 (one subject), or 0.075 mg/kg of aldicarb in orange juice during a 13 light breakfast. Females received 0, 0.025, or 0.05 mg/kg under the same protocol. Clinical 14 signs and symptoms were observed by trained researchers. Blood plasma and erythrocytes were 15 analyzed for cholinesterase activity at 1, 2, 4, 6, 8, and 21 hours after dosing; these values were 16 compared with each subject’s pre-exposure values taken at -16 and -3 hours and immediately 17 predose. Peak effects were noted at 1 hour after the dose. Males, but not females developed 18 symptoms consistent with acetylcholinesterase activity inhibition. In males, erythrocyte 19 cholinesterase activity at one hour was inhibited by 3.8, 12, 29, and 38% in the 0.01, 0.025, 20 0.050, and 0.075 mg/kg dose groups, respectively. In females, the mean inhibition at one hour 21 post-dose was 20% at 0.025 mg/kg and 36% at 0.050 mg/kg. The U.S. EPA noted that the 22 erythrocyte cholinesterase activity inhibition may have been underestimated due to lack of 23 measurement of some membrane-bound enzyme. The U.S. EPA considered the LOAEL 0.25 24 mg/kg based on sweating in one male. The NOAEL was 0.01 mg/kg. However, the Human 25 Studies Review Board (HSRB 2006) considered acetylcholinesterase activity inhibition a more 26 reliable endpoint than clinical signs. The HSRB (2006) reviewed the study and found it met 27 ethical considerations (required by EPA’s Human Subjects Protection Rule). 28

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1 3. ANIMAL TOXICITY DATA 2 3 Using protocols that were standard at the time, aldicarb was tested for dermal and ocular 4 irritation in the rabbit, and dermal sensitization in the guinea pig (IPCS 1991). Aldicarb was not 5 irritating to the skin (500 mg moistened in saline solution) or eye (0.1 mL of a 25% suspension 6 in propylene glycol). There was no sensitization response in male guinea pigs. Dermal LD50 7 doses in rats range from 2.5 to 3 mg/kg (Risher et al. 1987). Ranges for oral LD50 values for 8 aldicarb, aldicarb sulfoxide, and aldicarb sulfone in the rat are 0.62-1.23, 0.49-1.13, and 20-25 9 mg/kg body weight, respectively (IPCS 1992). The LOAEL for acute oral neurotoxicity in rats 10 was 0.05 mg/kg/day based on 23% and 10% inhibition of whole blood and erythrocyte 11 cholinesterase activity, respectively in female rats (U.S. EPA 2005). 12 13 3.1. Acute Toxicity 14 15 Early inhalation studies were summarized in several reviews including Risher et al. 16 (1987) and IPCS (1991). These summaries lacked details of exposure conditions and number 17 and sex of animals. Carpenter and Smyth (1965) conducted inhalation studies with rats, mice, 18 and guinea pigs. A concentration of 200 mg/m3 aldicarb dust was lethal to all species within 5 19 minutes. Rats and mice were more sensitive than guinea pigs. Rats survived a dust 20 concentration of 6.7 mg/m3 for 15 minutes, but five of six rats died after a 30-minute exposure. 21 All rats survived a saturated vapor concentration (not further described) for 8 hours. Two of six 22 rats survived an 8-hour exposure to an aerosol concentration of 7.6 mg/m3 (Weil and Carpenter 23 1970). Studies are summarized in Table 2. 24 25 Groups of five male and five female Sprague-Dawley rats inhaled an aerosol of aldicarb 26 solution in dichloromethane for 4 hours (UCC 1985). Measured concentrations of aldicarb were 27 0.82, 2.0, 6.0, 8.7, and 46.3 mg/m3. The respective mean dichloromethane concentrations for the 28 same exposures were 43, 94, 183, 25, and 100 mg/m3. The dichloromethane concentrations were 3 29 considered low in toxicity compared to aldicarb [LC50 values of 57,000-60,000 mg/m in rats and 30 mice (NTP 1986)]. The mass median aerodynamic diameter ranged from 2.0 to 3.8 µ. Ataxia 31 and tremors were seen at all concentrations during exposure. Additional signs of hypoactivity, 32 increased respiration rate, lacrimation, exophthalmos, and periocular encrustation were observed 33 at the two higher concentrations. Mortalities were seen at all concentrations except the lowest, 34 0.82 mg/m3. Mortalities in males were 0/5, 0/5, 3/5, 5/5, and 5/5, respectively. Mortalities in 3 35 females were 0/5, 1/5, 2/5, 5/5, and 5/5, respectively. The 4-hour LC50 was 3.9 mg/m with 36 confidence limits of 2.8-5.5 mg/m3. At necropsy, discoloration of the lungs, perinasal 37 encrustation and staining and eye abnormalities were observed. Survivors initially lost body 38 weight, but body weight gains were observed by the end of the 14-day post-exposure observation 39 period. 40 41 In studies conducted by Union Carbide Corporation from 1973-1977 (summarized in 42 UCC 1992), rats were also exposed to the degradate aldicarb sulfone (Temik® sulfone). An 43 aerosol of 120 mg/m3, 0.5% in distilled water, for 8 hours failed to induce lethality in six rats. 3 44 The LC50 for a 4-hour inhalation exposure to aldicarb sulfone dust was 420 mg/m . However, in 3 45 the same summary report, a 4-hour LC50 for rats of 120 mg/m was reported. Signs observed 46 during exposure were indicative of cholinesterase activity inhibition and, at necropsy, congestion 47 and hemorrhage of the lungs were noted.

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1 2 Additional aerosol studies with aldicarb sulfone were conducted (UCC 1992). An 3 aerosol of 6.9% technical aldicarb sulfone in dimethyl sulfoxide (approximately 2 mg/L) was 4 lethal to half of tested rats in 47.6 minutes whereas an aerosol of 0.5% in DMSO (approximately 5 184 mg/m3) was lethal to one of six rats in 4 hours. An aerosol of 0.5% in water (approximately 6 148 mg/m3) was not lethal to any of six rats in 4 hours. Signs of cholinesterase activity 7 inhibition were seen during exposure. 8 9 TABLE 2. Acute Toxicity of Aldicarb to Rats

Effect/LC50 Concentration (mg/m3) Exposure Duration (mg/m3) Reference Dust 6.7 15 minutes Survival: 6 of 6 Risher et al. 1987 30 minutes mortality: 5 of 6 Liquid Aerosol 0.82a 4 hours No mortality UCC 1985 2.0 mortality: 1 of 10 6.0 mortality: 5 of 10 8.7 mortality: 10 of 10 46.3 mortality: 10 of 10 3.9 calculated LC50 Vapor Saturated vapor No mortality – 8 hours ─ Risher et al. 1987 10 a Aldicarb aerosol solutions in dichloromethane. 11 12 3.2. Repeat-Exposure Studies 13 14 No repeat-exposure inhalation studies with aldicarb were located. In a nine-day repeat- 15 exposure inhalation study, groups of six male and six female Wistar rats inhaled 0, 1.4, 6, or 18 16 mg/m3 of the metabolite aldicarb sulfone as particulates for 6 hours/day for 9 days (UCC 1977; 17 U.S. EPA 1992). The test material was a 75% wettable powder. “Dust clouds” were generated 18 by a baffled dust feed through which air was passed at 20 liters/minute. Airborne dust 19 concentrations were measured gravimetrically. Exposure took place in a 120-L Plexiglas 20 chamber. Body weight was measured and liver, kidney and brain were weighed. Plasma, 21 erythrocyte, and brain were assayed for cholinesterase activity levels. No clinical signs were 22 evident in rats inhaling 1.4 or 6 mg/m3; there were no effects on body or organ weight. Rats 23 inhaling 18 mg/m3 displayed tremor and salivation. Body weight was decreased and blood 24 cholinesterase activity was significantly inhibited at 19 hours following termination of the 25 experiment (data not presented). Correction for percent active ingredient in the test material was 26 not mentioned. 27 28 3.3. Neurotoxicity 29 30 Acute toxicity studies showed that aldicarb is neurotoxic. Ataxia and tremors were 31 observed in rats inhaling aldicarb for 4 hours (UCC 1985). See Section 4.2 for mechanism of 32 toxicity of N-methyl carbamates. 33

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1 3.4. Developmental/Reproductive Toxicity 2 3 No inhalation studies were conducted that addressed the developmental or reproductive 4 toxicity of aldicarb. Reproductive and developmental toxicity studies that used the oral route of 5 administration were reviewed by Risher et al. (1987), IPCS (1991), and HSDB (2005). In 6 developmental studies with the rat and rabbit, aldicarb showed neither developmental toxicity 7 nor teratogenicity. Fetotoxicity manifest as reduced litter weight was apparent at maternally 8 toxic doses in Sprague Dawley rats (0.5 mg/kg/day from gestation days 6-15). No congenital 9 malformations were observed in offspring of rats administered aldicarb in the diet at 10 concentrations up to 1.0 mg/kg throughout pregnancy, or in offspring of Dutch Belted rabbits 11 administered aldicarb by gavage at doses up to 0.50 mg/kg on days 7 through 27 of gestation. 12 No reproductive parameters were affected in any of three generations of rats fed aldicarb in the 13 diet at doses up to 0.7 mg/kg body weight per day. 14 15 3.5. Genotoxicity 16 17 The genetic toxicology of aldicarb was reviewed by the National Toxicology Program 18 (NTP 1979) and the International Program on Chemical Safety (IPCS 1991). Bacterial assays 19 were conducted with and without metabolic activation. Assay results were negative for 20 mutagenicity in Salmonella typhimurium (TA97, TA100, TA1535, and TA1537) and 21 Escherichia coli WP2 uvrA. In an in vitro test for gene mutation in mouse L5178Y lymphoma 22 cells, results were inconclusive in the absence of metabolic activation, but aldicarb induced 23 mutations in the presence of S9 mix. Assays with aldicarb were negative for chromosome and 24 chromatid breaks in human peripheral lymphocytes, but a significant increase in sister chromatid 25 exchanges was seen in the same system. In in vivo clastogenicity assays, intraperitoneal 26 injections with aldicarb induced damage in bone marrow cells in rats, but not in mice. There 27 was no increased incidence of dominant lethal mutations in male rats treated with aldicarb in the 28 diet and mated with untreated virgin females. 29 30 3.6. Chronic Toxicity/Carcinogenicity 31 32 Technical aldicarb was tested for chronic toxicity and carcinogenicity in two-year dietary 33 studies with male and female F344 rats and B6C3F1 mice (NTP 1979). Groups of 50 rats and 50 34 mice of each sex were administered aldicarb in the diet at concentrations of 0, 2, or 6 ppm for 35 103 weeks and then observed for an additional 0 to 2 weeks. Body weight and survival were 36 unaffected in both rats and mice. Dosed mice appeared hyperactive. No tumors occurred in 37 either rats or mice at incidences that could clearly be related to administration of aldicarb. 38 39 Because the cholinesterase activity inhibition caused by aldicarb exposure is transient, 40 the U.S. “EPA had concluded that the cumulative risks associated with the N-methyl carbamate 41 pesticides are below the Agency’s level of concern” (U.S. EPA 2007a). 42 43 3.7. Summary 44 45 Acute inhalation lethality studies were conducted primarily with the rat. The 4-hour LC50 46 value for an aerosol of aldicarb in dichloromethane was 3.9 mg/m3 (UCC 1985). During 47 exposure rats showed signs of cholinesterase activity inhibition. No rats died following a 15-

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1 minute exposure to 6.7 mg/m3 aldicarb dust, but mortality was 100% after 30 minutes (Risher et 2 al. 1987). No details were available in the latter study. 3 4 Although considered highly acutely toxic, evidence indicates aldicarb does not affect 5 fetal development, impair reproductive performance, conclusively induce genotoxic effects, or 6 produce significant subchronic or chronic effects including cancer. 7 8 4. SPECIAL CONSIDERATIONS 9 4.1. Metabolism and Disposition 10 11 Inhalation studies with aldicarb that addressed metabolism were not located. The N- 12 methyl carbamates do not have a port of entry effect, are expected to be rapidly absorbed, and do 13 not require activation (U.S. EPA 2007b). Oral absorption is rapid and nearly complete (Risher et 14 al. 1987; IPCS 1991; AIHA 1993). The metabolic fate of aldicarb is similar in all species 15 examined (IPCS 1992). Clinical signs in rats appear at approximately 5 minutes after 16 administration. Unlike some organophosphate pesticides that are metabolized by A-esterases 17 which show great inter-individual variation, the metabolism of the carbamate pesticide aldicarb 18 involves both hydrolysis of the carbamate ester (to aldicarb oxime) and oxidation of the sulfur to 19 the sulfoxide and sulfone derivatives. Hydrolysis is a minor pathway and results in compounds 20 with little or no insecticidal activity (aldicarb oxime and aldicarb nitrile). Aldicarb is S-oxidized 21 by flavin-containing monooxygenases to form aldicarb sulfoxide (Tang et al. 2006). Aldicarb 22 sulfoxide is slowly degraded by both oxidative and hydrolytic mechanisms to yield the 23 corresponding aldicarb sulfone and sulfoxide oxime. The sulfoxide and sulfone metabolites are 24 active cholinesterase inhibitors. Excretion of these metabolites takes place via the urine (80- 25 90%) within the first 24-hours post-exposure. The major urinary metabolites are aldicarb 26 sulfoxide (40% of the dose) and aldicarb sulfoxide oxime and nitriles (over 30% of the dose). 27 Only a small amount is expired as CO2. Half-lives in rats and humans following oral dosing are 28 1.1 and 1.7 hours, respectively. Absorption through the skin can be extensive, and dermal LD50 29 doses in rats range from 2.5 to 3 mg/kg (Risher et al. 1987). 30 31 4.2. Mechanism of Toxicity 32 33 Aldicarb is an N-methyl carbamate insecticide. The mode of action of carbamate 34 pesticides involves cholinesterase inhibition (U.S. EPA 2007b; Costa 2008). Carbamic acid 35 esters attach to the serine hydroxyl group of the active site of acetylcholinesterase, the enzyme 36 responsible for the destruction and termination of the biological activity of the neurotransmitter 37 acetylcholine. When unbound acetylcholine accumulates at the cholinergic nerve endings, there 38 is continual stimulation of electrical activity. The resulting signs of toxicity from stimulation of 39 the muscarinic receptors of the parasympathetic autonomic nervous system are manifest as 40 increased secretions, bronchoconstriction, miosis, gastrointestinal cramps, diarrhea, urination, 41 and bradycardia. Stimulation of the parasympathetic junctions of the autonomic nervous system 42 as well as the junctions between nerves and muscles cause tachycardia, hypertension, muscle 43 fasciculation, tremors, muscle weakness, and flaccid paralysis. Signs and symptoms resulting 44 from effects on the central nervous system include restlessness, emotional lability, ataxia, 45 lethargy, mental confusion, loss of memory, generalized weakness, convulsions, cyanosis, and 46 coma. Inhibition of acetylcholinesterase activity is transient and rapidly reversible (minutes to 47 hours) because there is rapid reactivation of the carbamylated enzyme in the presence of water.

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1 Maximum inhibition typically occurs between 15 and 45 minutes after exposure. The major 2 metabolites of aldicarb, aldicarb sulfoxide and aldicarb sulfone are also cholinesterase inhibitors 3 (Risher et al. 1987; U.S. EPA 2007a). Aldicarb sulfoxide is considered to have similar potency 4 to the parent in terms of toxicity, while aldicarb sulfone is less potent. At the maximally 5 tolerated oral doses of 0.18, 0.26, and 0.35 mg/kg for PND 17, PND 27, and adult rats, brain 6 cholinesterase activity was 30-40% of the control value and blood cholinesterase activity was 7 <10% of the control value (Moser 1999). 8 9 Carbamates also inhibit butylcholinesterase, the primary form of cholinesterase found in 10 blood plasma. The toxicological significance of butylcholinesterase activity inhibition is 11 unknown. Acetylcholinesterase is the primary form of cholinesterase found in erythrocytes and 12 is present at neuromuscular and nerve-nerve junctions. A review of studies submitted to U.S. 13 EPA (2007b) for pesticide registration show that clinical signs and behavioral effects are not 14 evident below 10% cholinesterase activity inhibition. Due to human variability, it is difficult to 15 measure inhibition of <20% (U.S. EPA 2000). At greater than 30% erythrocyte 16 acetylcholinesterase activity inhibition or 50% plasma activity inhibition, workers are withdrawn 17 from pesticide application areas (U.S. EPA 2000; ACGIH 2008). Other enzymes such as 18 carboxylesterases are non-target enzymes to which cholinesterase activity inhibitors such as 19 aldicarb may bind. 20 21 4.3. Structure-Activity Relationships 22 23 Organophosphate and carbamate pesticides have a common mode of action (Costa 2008). 24 Compared to organophosphate ester pesticides, the carbamic acid esters are poor substrates for 25 cholinesterase-type enzymes. The carbamic acid esters which attach to the reactive site of acetyl 26 cholinesterase undergo fairly rapid hydrolysis, i.e., the carbamylated (inhibited) enzyme is 27 decarbamylated with the generation of the free, active enzyme. 28 29 Information is available on the relative oral toxicity of three carbamate pesticides (HSRB 30 2006; U.S. EPA 2007b). Aldicarb is considered the most toxic of the N-methyl carbamates. 31 Based on an assigned potency of 1 for oxamyl, aldicarb is considered 4 times more toxic by the 32 oral route. The endpoints for relative oral toxicity were brain and erythrocyte cholinesterase 33 activity inhibition in the rat and erythrocyte acetylcholinesterase activity inhibition in humans. 34 Raw data on erythrocyte cholinesterase activity inhibition were not provided for all three 35 chemicals, but relative toxicity can be derived from the benchmark doses (BMD10 and BMDL10) 36 calculated by U.S. EPA (2007b) from a range of oral doses (Table 3). For methomyl and 37 oxamyl, rat data on brain and erythrocyte cholinesterase activity are from McDaniel et al. 38 (2007). 39

TABLE 3. Adult Rat and Human BMD10 and BMDL10 Values for Cholinesterase Activity Inhibition for N- Methyl Carbamate Pesticides (Oral Dosing) Rat Human Brain Erythrocyte Erythrocyte Chemical Benchmark Half-life Benchmark Half-life Benchmark Half-life Dose (mg/kg) (h) Dose (mg/kg) (h) Dose (mg/kg) (h)

Aldicarb BMD10: 0.052 1.5 BMD10: 0.031 1.1 BMD10: 0.016 1.7 BMDL10: 0.035 BMDL10: 0.020 BMDL10: 0.013 Methomyl BMD10: 0.486 1.0 BMD10: 0.204 0.8 BMD10: 0.040 1.6

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BMDL10: 0.331 BMDL10: 0.112 BMDL10: 0.028 Oxamyl BMD10: 0.165 0.9 BMD10: 0.278 0.8 BMD10: 0.083 2.4 BMDL10: 0.127 BMDL10: 0.158 BMDL10: 0.068 1 Benchmark dose data for brain cholinesterase data for aldicarb and oxamyl are presented as the average of male and 2 female rat values. 3 The BMDL10 for 10% brain cholinesterase activity inhibition was used as the point of departure for U.S. EPA 4 (2007b) risk assessment. 5 Source: Table 1.B-9, U.S. EPA 2007b. 6 7 The major metabolites of aldicarb also have anticholinesterase activity. Compared to 8 oxamyl’s potency of 1, aldicarb, aldicarb sulfone, and aldicarb sulfoxide were assigned potencies 9 of 4, 3.44, and 3.68, respectively (U.S. EPA 2007b). These potencies were based on molecular 10 weight conversions from aldicarb. 11 12 4.4. Other Relevant Information 13 4.4.1. Species Variability 14 15 Inhalation studies with usable data were conducted only with rats. The extent of 16 hydrolysis of carbamate ester insecticides varies among species, ranging from 30 to 95%, and is 17 chemical specific (Costa 2008). Baseline erythrocyte acetylcholinesterase activity is higher in 18 humans than in other species (Ellin 1981). The U.S. EPA Office of Pesticide Programs (Taylor 19 and Reaves 2006) compared erythrocyte cholinesterase activity inhibition in human and adult rat 20 oral dosing studies following equivalent oral doses. Enzyme activity was assayed at 1 hour post- 21 dose in humans and 0.75 hours post-dose in rats (Table 4). 22 TABLE 4. Comparison of Erythrocyte Acetylcholinesterase Activity Inhibition in Rats and Humans Species Oral Dose 0.01 mg/kg 0.025 mg/kg 0.05 mg/kg Human (acute) Males 3.8% 12% 29% Females ─ 20% 36% Rat (acute) Males ─ ─ ─ Females ─ ─ 10% Rat (subchronic) Males ─ ─ 32% Females ─ ─ 24% 23 Source: Taylor and Reaves 2006. 24 25 The U.S. EPA Office of Pesticide Programs (2007b) compared the toxicity (endpoint 26 cholinesterase activity inhibition) of three N-methyl carbamate pesticides, oxamyl, methomyl, 27 and aldicarb, using oral dosing in humans and in juvenile and adult rats. Most data were 28 available for oxamyl which was used as the index chemical. Benchmark doses were calculated 29 for brain and erythrocyte cholinesterase activity inhibition in juvenile and adult rats and 30 erythrocyte cholinesterase activity inhibition in humans. Based on the comparative erythrocyte 31 acetylcholinesterase activity inhibition for equal oral doses in adult rats and humans, the U.S. 32 EPA calculated a chemical-specific interspecies uncertainty factor for aldicarb of 2. For most of 33 the N-methyl carbamate pesticides, the interspecies uncertainty factor is used for all routes of 34 exposure. 35

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1 4.4.2. Susceptible Populations 2 3 Humans are known to vary by gender, age, and genetic make-up in sensitivity to 4 cholinesterase inhibitors. The erythrocyte acetylcholinesterase activity of adults (153±24 5 activity units; acetylthiocholine substrate) is greater than that of healthy newborn infants (97±15 6 activity units) by a factor of 1.6 (Herz et al. 1975). Developmental neurotoxicity studies showed 7 that protection of the rat dam against cholinesterase activity inhibition is protective against pup 8 acetylcholinesterase activity inhibition in utero. 9 10 The U.S. EPA (2007b) identified infants and juveniles as the population most susceptible 11 to the toxicity of carbamate pesticides. In the absence of human data, the relative sensitivity to 12 cholinesterase activity inhibition of adult and juvenile rats to aldicarb can be used as a surrogate 13 for a comparison of human adult and infant sensitivity. Using the oral route of exposure, Moser 14 (1999) evaluated age-related differences in sensitivity to aldicarb among preweanling (post-natal 15 day 17 [PND 17]), postweanling (PND 27) and adult (PND 70) Long Evans rats of both sexes. 16 Control data for cholinesterase activity (nmol 3H-labeled acetylcholine iodide 17 hydrolyzed/min/mg/tissue) were (a) male brain: PND 17, 5.9; PND 27, 5.8; adult 7.0; male 18 blood: PND 17, 0.44; PND 27; 0.49, adult, 0.43; (b) female brain: PND 17, 4.9, PND 27, 6.1; 19 adult 6.9; female blood: PND 17, 0.50; PND 27, 0.52; adult, 0.59. Range-finding studies 20 determined the maximally tolerated doses (0.18, 0.26, and 0.35 mg/kg in the PND 17, 27, and 70 21 groups, respectively) and time of peak effect of blood cholinesterase activity inhibition, 1 hour in 22 all age groups. The U.S. EPA standard functional observational battery (FOB) and motor 23 activity observations were carried out. Pre-weanling rats were twice as sensitive to aldicarb as 24 adult rats, and dose-response data for brain acetylcholinesterase activity inhibition followed a 25 similar pattern of age-related differences. Blood cholinesterase activity inhibition measured with 26 a radiometric assay was greater than that of brain, with little age difference. At similar levels of 27 brain cholinesterase activity inhibition, young rats generally showed fewer signs of toxicity as 28 indicated by neurobehavioral parameters and motor activity than adult rats. 29 30 The U.S. EPA evaluated the relative sensitivity of juvenile and adult rats to N-methyl 31 carbamate pesticides including aldicarb (U.S. EPA 2007b). The U.S. EPA calculated benchmark 32 doses for brain cholinesterase activity inhibition in PND 17 and adult rats. The BMD10 and 33 BMDL10 in post-natal day 17 rats were 0.017 and 0.016 mg/kg, respectively. The BMD for adult 34 rats was 0.033 mg/kg. Based on comparative brain acetylcholinesterase activity inhibition in 35 aldicarb-treated post-natal day 17 juvenile rats and adult rats, the U.S. EPA calculated a Food 36 Quality Protection Act (FQPA) uncertainty factor for children of 2.0. This uncertainty factor 37 corresponds to an AEGL intraspecies uncertainty factor. A recovery half-life for brain 38 cholinesterase activity was not available for rats, but recovery was complete in juvenile and adult 39 rats by 24 hours (Moser 1999). 40 41 4.4.3. Concentration-Exposure Duration Relationship 42 43 No data were available for evaluating the relationship between ambient concentrations of 44 aldicarb and exposure duration for a single endpoint. The concentration-time relationship for a 45 single endpoint for many irritant and systemically acting vapors and gases may be described by 46 Cn x t = k (ten Berge et al. 1986). In the absence of empirical data, the time scaling factors of n

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1 = 3 and n = 1 are used to scale to shorter and longer exposure durations, respectively (NRC 2 2001). 3 4 4.4.4. Concurrent Exposure Issues 5 6 Dermal absorption may occur. Dermal LD50 values in rats range from 2.5 to 3.0 mg/kg 7 (Risher et al. 1987). Concurrent exposure to other N-methyl carbamates in proportion to their 8 potency indicates that they follow a dose-additive model of brain cholinesterase inhibition 9 (Padilla et al. 2006; U.S. EPA 2007b). 10 11 5. DATA ANALYSIS FOR AEGL-1 12 5.1. Summary of Human Data Relevant to AEGL-1 13 14 No human inhalation studies were located in the available literature. No occupational 15 monitoring data were presented by U.S. EPA (2007a). 16 17 5.2. Summary of Animal Data Relevant to AEGL-1 18 19 No inhalation studies were located that addressed signs consistent with the definition of 20 the AEGL-1. 21 22 5.3. Derivation of AEGL-1 23 24 No human or animal studies were located that addressed symptoms and signs consistent 25 with the definition of the AEGL-1. Therefore, AEGL-1 values are not recommended (Table 5). 26 TABLE 5. AEGL-1 Values for Aldicarb 10-min 30-min 1-h 4-h 8-hour Not recommended Not recommended Not recommended Not recommended Not recommended 27 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 28 29 6. DATA ANALYSIS FOR AEGL-2 30 6.1. Summary of Human Data Relevant to AEGL-2 31 32 No human inhalation studies relevant to development of AEGL-2 values were located in 33 the available literature. 34 35 6.2. Summary of Animal Data Relevant to AEGL-2 36 37 No animal studies relevant to deriving AEGL-2 values were located in the available 38 literature. All studies reviewed in Section 3.1 involved mortality. 39 40 6.3. Derivation of AEGL-2 41 42 No human or animal data on an aldicarb concentration that would result in effects 43 consistent with the definition of AEGL-2 were located. Therefore, consistent with Standard 44 Operating Procedures (NRC 2001), the AEGL-2 values were derived by dividing the AEGL-3

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1 values by 3. This approach is justified when there is a steep concentration-response curve. As 2 shown by Risher et al. (1987) mortality went from 0 to 83% with the doubling of exposure 3 duration. In the study reported by UCC (1985) mortality went from 10% at 2.0 mg/m3 to 50% 4 when concentration was increased 3-fold (6 mg/m3). AEGL-2 values are summarized in Table 6. 5 Calculations are in Appendix A and a category graph of the toxicity data in relation to AEGL 6 values is in Appendix B. 7 TABLE 6. AEGL-2 Values for Aldicarb 10-min 30-min 1-h 4-h 8-h 0.16 mg/m3 0.11 mg/m3 0.087 mg/m3 0.053 mg/m3 0.027 mg/m3 8 9 10 7. DATA ANALYSIS FOR AEGL-3 11 7.1. Summary of Human Data Relevant to AEGL-3 12 13 No human inhalation studies relevant to derivation of AEGL-3 values were located in the 14 available literature. 15 16 7.2. Summary of Animal Data Relevant to AEGL-3 17 18 A study with aldicarb dust lacked details of exposure and was of a short duration (Risher 19 et al. 1987). Vapor concentrations high enough to induce mortality were not attained in a second 20 study reported by Risher et al. (1987). One 4-hour study with aldicarb administered as an 21 aerosol in dichloromethane presented concentration-response information (UCC 1985). In that 22 study, mortality in rats inhaling 0.82, 2.0, 6.0, 8.7, or 46.3 mg/m3 was 0/10, 1/10, 5/10, 10/10, 23 and 10/10, respectively. 24 25 7.3. Derivation of AEGL-3 26 27 The study with aldicarb aerosol was chosen as the key study for AEGL-3 development 28 (UCC 1985). The 4-hour study used a sufficient number of rats and five concentrations. The 3 3 29 calculated 4-hour BMCL05 is 0.97 mg/m and the BMC01 is 1.9 mg/m (Appendix C). The 30 NAC/AEGL Committee generally uses the BMCL05 as the estimate at which lethality is not 31 likely to be observed (NRC 2001). The 4-hour 0.97 mg/m3 value was divided by inter- and 32 intraspecies uncertainty factors of 2 and 3, respectively, for a total of 6. U.S. EPA (2007b) 33 derived an uncertainty factor of 2 for aldicarb based on differences in modeled values for red 34 blood cell acetylcholinesterase activity inhibition between rats and humans (See section 4.4.1). 35 Based on comparative brain cholinesterase activity inhibition in post-natal day 17 juvenile rats 36 and adult rats, the U.S. EPA calculated an uncertainty factor of 2 to protect sensitive young (See 37 section 4.4.2). In keeping with intraspecies uncertainty factors applied to the related carbamate 38 pesticides, oxamyl and methomyl, the intraspecies uncertainty factor was raised to 3. The 39 combined uncertainty factor is 6. No differences were found in sensitivity between male and 40 female rats (UCC 1985). Values were time-scaled (Cn x t = k) from the 4-hour data point using n 41 values of 3 and 1 for extrapolation to shorter and longer exposure durations, respectively (NRC 42 2001). Values are summarized in Table 7, calculations are in Appendix A, and a category graph 43 of the toxicity data in relation to AEGL values is in Appendix B.

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1 TABLE 7. AEGL-3 Values for Aldicarb 10-min 30-min 1-h 4-h 8-h 0.47 mg/m3 0.32 mg/m3 0.26 mg/m3 0.16 mg/m3 0.081 mg/m3 2 3 When AEGL-3 values are based on a 4-hour or longer exposure duration, the 10-minute 4 value is usually set equal to the 30-minute value. However, the 15-minute value of 6.7 mg/mg3 5 for aldicarb dust that resulted in no mortality in rats can be used as justification for not setting 6 the 10- and 30-minute values equal. Application of a total uncertainty factor of 6 to the 6.7 7 mg/m3 value results in a 15-minute value of 1.1 mg/m3. The 15-minute value time-scaled to 10 8 minutes (n = 3) with application of an uncertainty factor of 6 is 1.3 mg/m3, a value considerably 9 larger than that derived from the 4-hour data. 10 11 The derived AEGL-3 values are based on an aerosol which may be less toxic than the 12 dust. Because the 15-minute value derived from dust is larger than the calculated number using 13 the aerosol, the use of the study with aerosol is justified. The dust study was not used for AEGL 14 derivation because of the short exposure period and single concentration. 15 16 8. SUMMARY OF AEGLs 17 8.1. AEGL Values and Toxicity Endpoints 18 19 AEGL values are summarized in Table 8. Derivations summaries are in Appendix C. 20 TABLE 8. Summary of AEGL Values for Aldicarb Exposure Duration Classification 10-min 30-min 1-h 4-h 8-h AEGL-1 Not Not Not Not Not (Nondisabling) recommended recommended recommended recommended recommended AEGL-2 0.16 mg/m3 0.11 mg/m3 0.087 mg/m3 0.053 mg/m3 0.027 mg/m3 (Disabling) AEGL-3 0.47 mg/m3 0.32 mg/m3 0.26 mg/m3 0.16 mg/m3 0.081 mg/m3 (Lethal) 21 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 22 23 8.2. Comparison with Other Standards and Guidelines 24 25 Standards and guidelines for aldicarb are listed in Table 9. The American Conference of 26 Government Industrial Hygienists (ACGIH) has not derived a Threshold Limit Value-Time 27 Weighted Average for aldicarb. The ACGIH has calculated a Biological Exposure Index for 28 acetylcholinesterase inhibiting chemicals (ACGIH 2008). The value, based on erythrocyte 29 cholinesterase activity inhibition, is 70% of an individual’s baseline. 30 31 The American Industrial Hygiene Association Workplace Environmental Exposure Level 32 Guide is 0.07 mg/m3 (AIHA 1993). This value corresponds to an inhaled amount of aldicarb of 33 0.01 mg/kg/day if one assumes inhalation of 10 m3 of air per 8-hour day by a 70-kg person. This 34 dose is judged to provide sufficient protection from adverse health effects. A skin notation is 35 recommended. 36

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TABLE 9. Standards and Guidelines for Aldicarb Exposure Duration Guideline 10 min 30 min 1 h 4 h 8 h AEGL-1 Not Not Not Not Not recommended recommended recommended recommended recommended AEGL-2 0.16 mg/m3 0.11 mg/m3 0.087 mg/m3 0.053 mg/m3 0.027 mg/m3 AEGL-3 0.47 mg/m3 0.32 mg/m3 0.26 mg/m3 0.16 mg/m3 0.081 mg/m3 ERPG-1 (AIHA)a ─ ERPG-2 (AIHA) ─ ERPG-3 (AIHA) ─ IDLH ─ (NIOSH)b REL-TWA ─ (NIOSH)c OSHA PEL ─ (NIOSH)d TLV-TWA ─ (ACGIH)e WEEL (AIHA)f 0.07 mg/m3 * MAK (Germany)g ─ MAC (The ─ Netherlands)h 1 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 2 * Skin notation. 3 4 aERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association 5 The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be 6 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 7 perceiving a clearly defined objectionable odor. 8 The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be 9 exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 10 symptoms that could impair an individual=s ability to take protective action. 11 The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be 12 exposed for up to one hour without experiencing or developing life-threatening health effects. 13 14 bIDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) 15 represents the maximum concentration from which one could escape within 30 minutes without any escape- 16 impairing symptoms, or any irreversible health effects. 17 18 cNIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - 19 Time Weighted Average) is defined analogous to the ACGIH-TLV-TWA. 20 21 dOSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time 22 Weighted Average) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 23 hours/day, 40 hours/week. 24 25 eACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 26 Time Weighted Average) is the time-weighted average concentration for a normal 8-hour workday and a 40-hour 27 workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. 28 29 fWEEL (Workplace Environmental Exposure Level Guide) (AIHA 1993) is the 8-hour time-weighted average 30 that is expected to be without adverse health effects during a normal 8-hour day and 40-hour workweek. 31 32 gMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche 33 Forschungsgemeinschaft [German Research Association] is defined analogous to the ACGIH-TLV-TWA.

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1 2 hMAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 3 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands is defined similar to the 4 ACGIH TLV. 5 6 8.3. Data Adequacy and Research Needs 7 8 Aldicarb has a low vapor pressure and no usable studies involving inhalation exposure of 9 humans were located in the available literature. An oral dosing study with human volunteers 10 addressed effects consistent with cholinesterase activity inhibition. Inhalation studies with rats 11 as the test species involving several exposure durations and dust, aerosol, and vapor delivery 12 were sufficient for derivation of two AEGL levels for five timepoints. Studies involving 13 comparisons of cholinesterase activity inhibition between juvenile and adult rats and between 14 rats and humans addressed chemical-specific uncertainty factors. Metabolism pathways and 15 mode of action are well understood. 16 17 9. REFERENCES 18 19 ACGIH (American Conference of Government and Industrial Hygienists). 2008. TLVs and BEIs Based 20 on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & 21 Biological Exposure Indices. Cincinnati, OH: ACGIH. 22 23 AIHA (American Industrial Health Association). 1993. Workplace Environmental Exposure Level 24 Guide: Aldicarb. Fairfax, VA: American Industrial Hygienists Association. 25 26 Carpenter, C.P. and H.F. Smyth. 1965. Recapitulation of pharmacodynamic and acute toxicity studies on 27 Temik. Mellon Institute unpublished report 28-75. (Reviewed in IPCS 1991). 28 29 Costa, L.G. 2008. Chapter 22: Toxic Effects of Pesticides. In Casarett & Doull’s Toxicology, The Basic 30 Science of Poisons. 7th Ed. New York: McGraw-Hill. 31 32 Ellin, R.I. 1981. Anomalies in theories and therapy of intoxication by potent organophosphorus 33 anticholinesterase compounds. U.S. Army Medical Research and Development Command, 34 Biomedical Laboratory Report No. USABML-SP-81-003. Available from the Defense Technical 35 Information Center, AD A1013364. 36 37 Herz, F., E. Kaplan, and E.S. Scheye. 1975. A longitudinal study of red cell enzymes in infants of low 38 birth weight. Z. Kinderheilk. 120: 217-221. 39 40 HSDB (Hazardous Substances Data Bank). 2005. Aldicarb. Available online: 41 http://toxnet/nlm.nih.gov/cgi-bin/sis/download.txt. 42 43 HSRB (Human Studies Review Board). 2006. Report of the Human Studies Review Board April 4-6, 44 2006, regarding chemicals aldicarb, methomyl, oxamyl, azinphos-methyl, DDVP, ethephon, 45 hydrogen cyanide, and amitraz. Available online: http://www.epa.gov/osa/hsrb/files/meeting- 46 materials/apr-4-6-2006-public-meeting/april2006mtgfinalreport62606.pdf. 47 48 IPCS (International Program on Chemical Safety). 1991. Environmental Health Criteria 121: Aldicarb. 49 World Health Organization. Available online: 50 http://www.inchem.org/documents/ehc/ehc/ehc121.htm. 51

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1 IPCS (International Program on Chemical Safety). 1992. Pesticide Residues in Food: 1992 Evaluations 2 Part II: Toxicology. World Health Organization. Available online: 3 http://www.inchem.org/documents/jmpr/jmpmono/v92pr03.htm. 4 5 McDaniel, K.L., S. Padilla, R.S. Marshall, P.M. Phillips, L. Podhorniak, Y. Qian, and V.C. Moser. 2007. 6 Comparison of acute neurobehavioral and cholinesterase inhibitory effects of N-methylcarbamates in 7 rat. Toxicol. Sci. 98:552-560. 8 9 Moser, V.C. 1999. Comparison of aldicarb and methamidophos neurotoxicity at different ages in the rat: 10 behavioral and biochemical parameters. Toxicol. Appl. Pharmacol. 157:94-106. 11 12 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute 13 Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. 14 15 NTP (National Toxicology Program). 1979. Bioassay of Aldicarb for Possible Carcinogenicity (CAS 16 No. 116-06-3). TR-136. Available online: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr136.pdf. 17 18 NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis Studies of Dichloromethane 19 (Methylene Chloride) (CAS No. 75-09-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 20 TR-No. 306. Available online: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr306.pdf 21 22 O’Neil, M.J., A. Smith, and P.E. Heckelman. 2001. Aldicarb. The Merck Index. Whitehouse Station, 23 NJ: Merck & Co., Inc., p. 224. 24 25 Padilla, S., W. Setzer, R.S. Marshall, D. Hunter, P. Phillips, K. McDaniel, V.C. Moser, and A. Lowit. 26 2006. A dose-response study of the toxicity of a mixture of 7 N-methyl carbamates in adult, male 27 rats. Presented at the 45th Annual Meeting of the Society of Toxicology, San Diego, CA. 28 29 Risher J.F., F.L. Mink, and J.F. Stara. 1987. The toxicologic effects of the carbamate insecticide aldicarb 30 in mammals: a review. Environ. Health Persp. 72:267-281. 31 32 Tang, J., R.L. Rose, and J.E. Chambers. 2006. Chapter 10: Metabolism of organophosphorus and 33 carbamate pesticides. Pp. 127-143 in Gupta, R.C. (ed) Toxicology of Organophosphate and 34 Carbamate Compounds. Elsevier Academic Press, Burlington, MA. 35 36 Taylor, L. and E. Reaves. 2006. Aldicarb: WOE Comparison of Human and Animal Studies for Single 37 Chemical Assessment and NMC Cumulative Assessment. Presentation, U.S. Environmental 38 Protection Agency, Office of Pesticide Programs, April 4, 2006. Available online. 39 40 ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response 41 relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13: 301-309. 42 43 UCC (Union Carbide Corporation). 1977. UC 21865-75WP: 2-Methyl-s-(methylsulfonyl) propanol O- 44 [(methylamino)carbonyl] oxime: results of nine-day inhalation study on rats, Project Report 40-29, 45 March 16, 1977, Carnegie-Mellon University. OTS0539433; ID 88-920002674, 1992, available from 46 National Technical Information Service, Springfield, VA. 47 48 UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC50 Aerosol Acute Inhalation 49 Toxicity Test. Bushy Run Research Center, Project Report 48-136, December 11, 1985. Initial 50 submission: Letter from Union Carbide Corp. to USEPA submitting enclosed information on aldicarb 51 solutions in dichloromethane aerosol inhalation and acute toxicity studies with attachment.

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1 Submission dated 1992. OTS0543711; ID 88-920006638, 1992, available from National Technical 2 Information Service, Springfield, VA. 3 4 UCC (Union Carbide Corporation). 1986. Material Safety Data Sheet: Aldicarb. Research Triangle 5 Park, NC: Union Carbide Agricultural Products Company, Inc. Available online. 6 7 UCC (Union Carbide Corporation). 1992. Initial Submission: Letter from Union Carbide submitting 8 reports describing a variety of toxicology studies with Temik Sulfone with attachments. OTS 9 0539433, available from the National Technical Information Center, Springfield, VA. 10 11 U.S. EPA (U.S. Environmental Protection Agency). 1992. Data Evaluation Report: Aldicarb. Review of 12 Wyld et al., (1992) A Safety and Tolerability Study of Aldicarb at Various Dose Levels in Healthy 13 Male and Female Volunteers. Available from U.S. EPA. 14 15 U.S. EPA (U.S. Environmental Protection Agency). 2000. Office of Pesticide Programs Science Policy 16 on The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorous and 17 Carbamate Pesticides. Washington, DC: U.S. Environmental Protection Agency. Available online: 18 http://www.epa.gov/pesticides/trac/science/cholin.pdf. 19 20 U.S. EPA (U.S. Environmental Protection Agency). 2005. Memorandum (TXR No. 0052688) from 21 Linda Taylor, Health Effect Division to Mika Hunter Special Review and Registration Division, 22 September 22, 2005. Available online. 23 24 U.S. EPA (U.S. Environmental Protection Agency). 2007a. Reregistration Eligibility Decision (RED) 25 for Aldicarb. Available online: www.epa.gov/pesticides/reregistration/REDs/aldicarb_red.pdf. 26 27 U.S. EPA (U.S. Environmental Protection Agency). 2007b. Revised N-Methyl Carbamate Cumulative 28 Risk Assessment. Office of Pesticide Programs. Available online: 29 http://www.epa.gov/oppsrrd1/REDs/nmc_revised_cra.pdf. 30 31 Weil, C.S. and C.P. Carpenter. 1970. Temik and other materials. Miscellaneous single dose peroral and 32 parenteral LD50 assays and some joint action studies. Unpublished Mellon Institute Report 33-7. 33 (Reviewed in IPCS 1991). 34 35 Wyld, P.J., C.E. Watson, W.S. Nimmo, and N. Watson. 1991. A Safety and Tolerability Study of 36 Aldicarb at Various Dose Levels in Healthy Male and Female Volunteers. Inveresk Clinical Research 37 Limited, Riccarton, Edinburgh, Scotland, Report No. 7786. (Reviewed in U.S. EPA 1992). 38

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1 2 APPENDIX A: Derivation of Aldicarb AEGLs 3 4 Derivation of AEGL-1 Values 5 6 No human or animal studies were located that addressed symptoms and signs consistent 7 with the definition of the AEGL-1. Therefore, AEGL-1 values are not recommended. 8 9 Derivation of AEGL-2 Values 10 11 Key Study: UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC50 12 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, 13 Project Report 48-136, December 11, 1985. 14 15 Toxicity endpoint: AEGL-3 values divided by 3. The steep concentration-response line shown 16 by the Risher et al. (1987) and UCC (1985) data justifies deriving AEGL-2 17 values by dividing the AEGL-3 values by 3 (NRC 2001). 18 19 Time scaling See AEGL-3 derivation, next page 20 21 Uncertainty factors: Total uncertainty factor: 6 (See AEGL-3 derivation, next page) 22 23 Calculations: AEGL-3 values divided by 3 24 25 10-min AEGL-2: C = 0.47 mg/m3/3 = 0.16 mg/m3 26 27 30-min AEGL-2: C = 0.32 mg/m3/3 = 0.11 mg/m3 28 29 1-h AEGL-2: C = 0.26 mg/m3/3 = 0.087 mg/m3 30 31 4-h AEGL-2: C = 0.16 mg/m3/3 = 0.053 mg/m3 32 33 8-h AEGL-2: C = 0.081 mg/m3/3 = 0.027 mg/m3 34 35 36

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1 2 Derivation of AEGL-3 Values 3 4 Key Study: UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC50 5 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, 6 Project Report 48-136, December 11, 1985. 7 3 8 Toxicity endpoint: Threshold for lethality in rats at the BMCL05 of 0.973753 mg/m calculated 9 from the rat lethality data of UCC (1985). 10 11 Time scaling Cn x t = k where n = 3 and 1 for shorter and longer exposure durations, 12 respectively (NRC 2001). 13 14 Uncertainty factors: Total uncertainty factor: 6 15 Interspecies: 2 – The U.S. EPA (2007b) Office of Pesticide Programs 16 calculated an oxamyl-specific inhalation interspecies uncertainty 17 factor of 2 based on differences in modeled red blood cell values for 18 cholinesterase activity inhibition between the rat and humans. 19 Intraspecies: 3 – The U.S. EPA (2007b) Office of Pesticide Programs 20 calculated an aldicarb-specific inhalation intraspecies uncertainty 21 factor of 2 based on comparative brain acetylcholinesterase activity 22 inhibition in post-natal day 17 juvenile rats and adult rats. For 23 consistency among the N-methyl carbamate pesticides, the chemical- 24 specific intraspecies uncertainty factor of 3, derived for the both of the 25 related N-methyl carbamate pesticides, oxamyl and methomyl, was 26 applied to aldicarb. 27 28 Modifying factor: None applied 29 30 Calculations: (0.973753 mg/m3/6)3 x 240 minutes = 1.03 mg/m3•min 31 32 10-min AEGL-3: C = 3√(1.03 mg/m3•min /10) = 0.47 mg/m3 33 34 30-min AEGL-3: C = 3√(1.03 mg/m3•min/30) = 0.32 mg/m3 35 36 1-h AEGL-3: C = 3√(1.03 mg/m3•min/60) = 0.26 mg/m3 37 38 4-h AEGL-3: C = 0.973753/6 = 0.16 mg/m3 39 40 8-h AEGL-3: C = (0.16 mg/m3•min x 240 min)/480 minn = 0.081 mg/m3 41 42 43

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1 APPENDIX B: Category Graph of AEGL Values and Toxicity Data 2 Category Graph - Animal Data Aldicarb

100.0

No Effect

10.0 Discomfort

Disabling 1.0 mg/m3 Some Lethality AEGL-3

0.1 Lethal

AEGL-2

AEGL

0.0 0 60 120 180 240 300 360 420 480 Minutes

3 4 5 6 Data: For Category: 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal Source Species mg/m3 Minutes Category

NAC/AEGL-1 Not recommended 10 AEGL NAC/AEGL-1 Not recommended 30 AEGL NAC/AEGL-1 Not recommended 60 AEGL NAC/AEGL-1 Not recommended 240 AEGL NAC/AEGL-1 Not recommended 480 AEGL

NAC/AEGL-2 0.16 10 AEGL NAC/AEGL-2 0.11 30 AEGL NAC/AEGL-2 0.087 60 AEGL NAC/AEGL-2 0.053 240 AEGL NAC/AEGL-2 0.027 480 AEGL

NAC/AEGL-3 0.47 10 AEGL NAC/AEGL-3 0.32 30 AEGL NAC/AEGL-3 0.26 60 AEGL NAC/AEGL-3 0.16 240 AEGL NAC/AEGL-3 0.081 480 AEGL

ALDICARB NAC Proposed 1: June 2009/ Page 26 of 33

Risher et al. 1987 rat 6.7 15 2; survival of 6 of 6 rat 6.7 30 SL; mortality of 5 of 6

UCC 1985 rat 0.82 240 2; ataxia and tremors rat 2.9 240 SL; mortality of 1 of 10 rat 6.0 240 SL; mortality of 5 of 10 rat 8.7 240 3; mortality of 10 of 10 rat 46.3 240 3; mortality of 10 of 10 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 1

ALDICARB NAC Proposed 1: June 2009/ Page 27 of 33

1 2 APPENDIX C: Benchmark Concentration Calculations for Aldicarb 3 4 Aldicarb BMCL05 Derivation (data of UCC 1985) 5 ======6 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ 7 Input Data File: C:\BMDS\BCME_RAT.(d) 8 Gnuplot Plotting File: C:\BMDS\BCME_RAT.plt 9 Wed Apr 15 18:17:01 2009 10 ======11 BMDS MODEL RUN 12 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 13 The form of the probability function is: 14 15 P[response] = Background 16 + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 17 18 where CumNorm(.) is the cumulative normal distribution function 19 20 Dependent variable = COLUMN3 21 Independent variable = COLUMN1 22 Slope parameter is not restricted 23 24 Total number of observations = 6 25 Total number of records with missing values = 0 26 Maximum number of iterations = 250 27 Relative Function Convergence has been set to: 1e-008 28 Parameter Convergence has been set to: 1e-008 29 30 User has chosen the log transformed model 31 Default Initial (and Specified) Parameter Values 32 background = 0 33 intercept = -1.49047 34 slope = 0.948882 35 36 Asymptotic Correlation Matrix of Parameter Estimates 37 38 ( *** The model parameter(s) -background have been estimated at a boundary point, or 39 have been specified by the user, and do not appear in the correlation matrix ) 40 41 intercept slope 42 intercept 1 -0.95 43 slope -0.95 1 44 Parameter Estimates 45 Variable Estimate Std. Err. 46 background 0 NA 47 intercept -2.82566 0.882065

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1 slope 1.84829 0.513275 2 3 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 4 has no standard error. 5 6 Analysis of Deviance Table 7 Model Log(likelihood) Deviance Test DF P-value 8 Full model -10.1823 9 Fitted model -12.333 4.30146 4 0.3667 10 Reduced model -41.0539 61.7432 5 <.0001 11 12 AIC: 28.6661 13 Goodness of Fit Scaled 14 Dose Est._Prob. Expected Observed Size Residual 15 ------16 0.0000 0.0000 0.000 0 10 0 17 0.8200 0.0007 0.007 0 10 -0.08401 18 2.0000 0.0612 0.612 1 10 0.5114 19 6.0000 0.6865 6.865 5 10 -1.271 20 8.7000 0.8796 8.796 10 10 1.17 21 46.3000 1.0000 10.000 10 10 0.01005 22 23 Chi-square = 3.25 DF = 4 P-value = 0.5161 24 25 Benchmark Dose Computation 26 Specified effect = 0.05 27 Risk Type = Extra risk 28 Confidence level = 0.95 29 30 BMC05 = 1.89433 31 BMCL05 = 0.973753

Probit Model with 0.95 Confidence Level

Probit 1

0.8

0.6

0.4 Fraction Affected 0.2

0 BMDL BMD 0 10 20 30 40 50 dose 32 18:17 04/15 2009

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1 Aldicarb BMC01 Derivation (data of UCC 1985) 2 ======3 Probit Model. (Version: 2.8; Date: 02/20/2007) 4 Input Data File: C:\BMDS\UNSAVED1.(d) 5 Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt 6 Tue Mar 10 07:28:32 2009 7 ======8 BMDS MODEL RUN 9 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 10 The form of the probability function is: 11 P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 12 where CumNorm(.) is the cumulative normal distribution function 13 14 Dependent variable = COLUMN3 15 Independent variable = COLUMN1 16 Slope parameter is not restricted 17 18 Total number of observations = 6 19 Total number of records with missing values = 0 20 Maximum number of iterations = 250 21 Relative Function Convergence has been set to: 1e-008 22 Parameter Convergence has been set to: 1e-008 23 24 User has chosen the log transformed model 25 Default Initial (and Specified) Parameter Values 26 background = 0 27 intercept = -1.49047 28 slope = 0.948882 29 30 Asymptotic Correlation Matrix of Parameter Estimates 31 32 ( *** The model parameter(s) -background have been estimated at a boundary point, or 33 have been specified by the user, and do not appear in the correlation matrix ) 34 35 intercept slope 36 intercept 1 -0.95 37 slope -0.95 1 38 39 Parameter Estimates 40 95.0% Wald Confidence Interval 41 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 42 background 0 NA 43 intercept -2.82566 0.882065 -4.55448 -1.09685 44 slope 1.84829 0.513275 0.842291 2.85429 45 46 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 47 has no standard error.

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1 Analysis of Deviance Table 2 Model Log(likelihood) # Param's Deviance Test d.f. P-value 3 Full model -10.1823 6 4 Fitted model -12.333 2 4.30146 4 0.3667 5 Reduced model -41.0539 1 61.7432 5 <.0001 6 7 AIC: 28.6661 8 9 Goodness of Fit Scaled 10 Dose Est._Prob. Expected Observed Size Residual 11 ------12 0.0000 0.0000 0.000 0 10 0.000 13 0.8200 0.0007 0.007 0 10 -0.084 14 2.0000 0.0612 0.612 1 10 0.511 15 6.0000 0.6865 6.865 5 10 -1.271 16 8.7000 0.8796 8.796 10 10 1.170 17 46.3000 1.0000 10.000 10 10 0.010 18 19 Chi^2 = 3.25 d.f. = 4 P-value = 0.5161 20 21 Benchmark Dose Computation 22 Specified effect = 0.01 23 Risk Type = Extra risk 24 Confidence level = 0.95 25 26 BMC01 = 1.31016 27 BMCL01 = 0.54285 28

Probit Model with 0.95 Confidence Level

Probit 1 BMD Lower Bound

0.8

0.6

0.4 Fraction Affected Fraction

0.2

0 BMDL BMD

0 10 20 30 40

dose 29 07:28 03/10 2009

ALDICARB NAC Proposed 1: June 2009/ Page 31 of 33

1 2 APPENDIX D: Derivation Summary for Aldicarb AEGLs 3 Acute Exposure Guideline Levels For Aldicarb 4 (CAS Reg. No. 23135-22-0) 5 AEGL-1 VALUES 10-min 30-min 1-h 4-h 8-hour Not recommended Not recommended Not recommended Not recommended Not recommended Key Reference: Insufficient data Test Species/Strain/Sex/Number: Exposure Route/Concentration/Duration: Effects: Endpoint/Concentration/Rationale: Uncertainty Factors/Rationale: Total uncertainty factor: Interspecies: Intraspecies: Modifying Factor: Animal to Human Dosimetric Adjustment: Time Scaling: Data Adequacy: 6 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 7

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1 AEGL-2 VALUES 10-min 30-min 1-h 4-h 8-h 0.16 mg/m3 0.11 mg/m3 0.087 mg/m3 0.053 mg/m3 0.027 mg/m3 Key Reference: UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC50 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, Project Report 48-136. Test Species/Strain/Number: Rat/Sprague-Dawley/groups of 5 per sex Exposure Route/Concentration/Duration: Inhalation/0.82, 2.0, 6.0, 8.7, 46.3 mg/m3/4 hours Effects: acetylcholinesterase activity inhibition, estimate at 1/3 of the AEGL-3 values. Endpoint/Concentration/Rationale: One-third of the AEGL-3 values, based on the steep concentration- response curve Uncertainty Factors/Rationale: Total uncertainty factor: 6 (used for derivation of AEGL-3) Interspecies: 2 Intraspecies: 3 Modifying Factor: None applied Animal to Human Dosimetric Adjustment: Not applicable Time Scaling: Cn x t = k, where n = 3 and 1 for shorter and longer exposure durations, respectively Data Adequacy: The key study was well conducted, used adequate numbers of rats, and five concentrations. 2 3 4

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1 AEGL-3 VALUES 10-min 30-min 1-h 4-h 8-h 0.47 mg/m3 0.32 mg/m3 0.26 mg/m3 0.16 mg/m3 0.081 mg/m3

Key References: UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC50 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, Project Report 48-136. Test Species/Strain/Number: Rat/Sprague-Dawley/groups of 5 per sex Exposure Route/Concentration/Duration: Inhalation/0.82, 2.0, 6.0, 8.7, 46.3 mg/m3/4 hours Effect: Mortalities: 0, 1, 5, 10, and 10

Endpoint/Concentration/Rationale: BMCL05, estimated as the threshold for lethality Uncertainty Factors/Rationale: Total uncertainty factor: 6 Interspecies: 2: The U.S. EPA (2007b) Office of Pesticide Programs calculated an aldicarb-specific interspecies uncertainty factor of 2 based on differences in values of modeled red blood cell cholinesterase activity inhibition between the rat and humans. Intraspecies: 3: The U.S. EPA (2007b) Office of Pesticide Programs calculated an aldicarb-specific intraspecies uncertainty factor of 3 for the related chemicals oxamyl and methomyl based on comparative brain acetylcholinesterase activity inhibition in post-natal day 17 juvenile rats and adult rats. Modifying Factor: None applied Animal to Human Dosimetric Adjustment: Not applicable Time Scaling: Cn x t = k, where n = 3 and 1 for shorter and longer exposure durations, respectively. Data Adequacy: The key study was well conducted, used adequate numbers of rats, and five concentrations. 2